The purpose of this Drug Discovery Program is to develop and screen drugs which will inhibit production and cytopathic effects of the AIDS retrovirus. The proposal combines the capabilities of several laboratory programs of established investigators with proven track record in drug synthesis, analytical pharmacology, experimental chemotherapy and retrovirology. The proposed program consists of four major areas covering drug synthesis, in vitro screening, biological studies and cellular pharmacology. We propose to evaluate a series of nucleoside analogs synthesized at the University of Miami and Birmingham,U.K, natural products isolated and characterized at the University of Arizona and a host of chemicals and culture filterates from UpJohn repository for their anti-viral and anti- viral polymerase activity. Selected drugs which show positive anti-viral and/or anti-viral polymerase activity will be further studied for their transport characteristics, metabolism and cytotoxicity against a panel of human cell lines. Besides these 4 major research areas, we have established 6 core resources to provide laboratory and administrative support to the participants. The overall program will rapidly translate information from all sources into new drug development. Particularly relevant to new drug discovery, the proposed group can evaluate clinical outcome in phase I and II studies in the NIH Drug Evaluation Unit at the University of Miami to validate the in vitro screening techniques. Jointly, the laboratory programs proposed represent an ambitious yet highly pragmatic approach to antiviral chemotherapy for AIDS at the same time as providing the basic research database essential for understanding the mechanisms of action of anti- AIDS' drugs.